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Film Coated Tablets
One tablet to be taken twice daily. Dose titration with pioglitazone should be considered before the patient is switched to this drug. When clinically appropriate, direct change from metformin monotherapy may be considered.
Elderly: Patients should have their renal function monitored regularly. Physicians should start treatment with the lowest available dose and increase the dose gradually, particularly when pioglitazone is used in combination with insulin.
Renal Impairment: Should not be used in patients with renal failure or renal dysfunction (creatinine clearance< 60 ml/min).
Hepatic Impairment: Should not be used in patients with hepatic impairment.
Paediatric Population: The safety and efficacy in children and adolescents under 18 years of age have not been established.
Method of Administration: Tablets should be swallowed with a glass of water. Taking with, or just after food, may reduce gastrointestinal symptoms associated with metformin.
Indicated as second line treatment of type 2 diabetes mellitus adult patients, particularly overweight patients, who are unable to achieve sufficient glycaemic control at their maximally tolerated dose of oral metformin alone.
After initiation of therapy with pioglitazone, patients should be reviewed after 3 to 6 months to assess adequacy of response to treatment (e.g. reduction in HbA1c). In patients who fail to show an adequate response, pioglitazone should be discontinued. In light of potential risks with prolonged therapy, prescribers should confirm at subsequent routine reviews that the benefit of pioglitazone is maintained.
Hypersensitivity to the active substances or to any of the excipients; Cardiac failure or history of cardiac failure (NYHA stages I to IV); Current bladder cancer or a history of bladder cancer; Uninvestigated macroscopic haematuria; Acute or chronic disease which may cause tissue hypoxia such as cardiac or respiratory; failure, recent myocardial infarction, shock; Hepatic impairment; Acute alcohol intoxication, alcoholism; Diabetic ketoacidosis or diabetic pre-coma; Renal failure or renal dysfunction (creatinine clearance <60 ml/min); Acute conditions with the potential to alter renal function such as: Dehydration, Severe infection, Shock; Intravascular administration of iodinated contrast agents; Breast-feeding.
There is no clinical experience of pioglitazone in triple combination with other oral antidiabetic medicinal products.
Lactic acidosis: Lactic acidosis is a very rare, but serious, metabolic complication that can occur due to metformin accumulation. Reported cases of lactic acidosis in patients on metformin have occurred primarily in diabetic patients with significant renal failure. The incidence of lactic acidosis can and should be reduced by assessing also other associated risk factors such as poorly controlled diabetes, ketosis, prolonged fasting, excessive alcohol intake, hepatic insufficiency and any condition associated with hypoxia.
Renal function: As metformin is excreted by the kidney, serum creatinine concentrations should be determined regularly:
– at least once a year in patients with normal renal function
– at least two to four times a year in patients with serum creatinine levels at the upper limits of normal and in elderly subjects.
Decreased renal function in elderly patients is frequent and asymptomatic. Special caution should be exercised in situations where renal function may become impaired, for example when initiating antihypertensive therapy or diuretic therapy and when starting treatment with a NSAID.
Fluid retention and cardiac failure: Pioglitazone can cause fluid retention, which may exacerbate or precipitate heart failure. When treating patients who have at least one risk factor for development of congestive heart failure (e.g. prior myocardial infarction or symptomatic coronary artery disease or the elderly), physicians should start with the lowest available dose and increase the dose gradually. Patients should be observed for signs and symptoms of heart failure, weight gain or oedema; particularly those with reduced cardiac reserve.
Elderly: Combination use with insulin should be considered with caution in the elderly because of increased risk of serious heart failure.
In light of age- related risks (especially bladder cancer, fractures and heart failure), the balance of benefits and risks should be considered carefully both before and during treatment in the elderly.
Bladder Cancer: Risk factors for bladder cancer should be assessed before initiating pioglitazone treatment (risks include age, smoking history, exposure to some occupational or chemotherapy agents e.g. cyclophosphamide or prior radiation treatment in the pelvic region). Any macroscopic haematuria should be investigated before starting pioglitazone therapy.
Patients should be advised to promptly seek the attention of their physician if macroscopic haematuria or other symptoms such as dysuria or urinary urgency develop during treatment.
Monitoring of liver function: There have been rare reports of elevated liver enzymes and hepatocellular dysfunction during post-marketing experience with pioglitazone. Although in very rare cases fatal outcome has been reported, causal relationship has not been established.
It is recommended, therefore, that patients treated with Competact undergo periodic monitoring of liver enzymes. Liver enzymes should be checked prior to the initiation of therapy with Competact in all patients. Therapy with Competact should not be initiated in patients with increased baseline liver enzyme levels (ALT > 2.5 X upper limit of normal) or with any other evidence of liver disease.
See prescribing information for full details.
At the initiation of the treatment abdominal pain, diarrhoea, loss of appetite, nausea and vomiting may occur, these reactions are very common but usually disappear spontaneously in most cases. Lactic acidosis is a serious reaction which may occur in less than 1 case per 10,000 patients and other reactions such as bone fracture, weight increase and oedema may occur in less than 1 case per 10 patients.
See prescribing information for full details.
There have been no formal interaction studies for Competact. The following statements reflect the information available on the individual active substances (pioglitazone and metformin).
Intravascular administration of iodinated contrast agents in radiological studies may lead to renal failure, resulting in metformin accumulation and risk of lactic acidosis. Metformin should be discontinued prior to, or at the time of the test and not reinstituted until 48 hours afterwards, and only after renal function has been re-evaluated and found to be normal.
There is increased risk of lactic acidosis in acute alcohol intoxication (particularly in the case of fasting, malnutrition or hepatic insufficiency) due to the metformin active substance of Competact. Avoid consumption of alcohol and medicinal products containing alcohol.
Cationic medicinal products that are eliminated by renal tubular secretion (e.g. cimetidine) may interact with metformin by competing for common renal tubular transport systems. A study conducted in seven normal healthy volunteers showed that cimetidine, administered as 400 mg twice daily, increased metformin systemic exposure (AUC) by 50% and Cmax by 81%.
Therefore, close monitoring of glycaemic control, dose adjustment within the recommended posology and changes in diabetic treatment should be considered when cationic medicinal products that are eliminated by renal tubular secretion are co-administered.
Co-administration of pioglitazone with gemfibrozil (an inhibitor of cytochrome P450 2C8) is reported to result in a 3-fold increase in AUC of pioglitazone. Since there is a potential for an increase in dose-related adverse events, a decrease in the dose of pioglitazone may be needed when gemfibrozil is concomitantly administered. Close monitoring of glycaemic control should be considered. Co-administration of pioglitazone with rifampicin (an inducer of cytochrome P450 2C8) is reported to result in a 54% decrease in AUC of pioglitazone. The pioglitazone dose may need to be increased when rifampicin is concomitantly administered.
Close monitoring of glycaemic control should be considered.
Glucocorticoids (given by systemic and local routes), beta-2-agonists, and diuretics have intrinsic hyperglycaemic activity. The patient should be informed and more frequent blood glucose monitoring performed, especially at the beginning of treatment. If necessary, the dosage of the antihyperglycaemic medicinal product should be adjusted during therapy with the other medicinal product and on its discontinuation.
ACE-inhibitors may decrease the blood glucose levels. If necessary, the dosage of the antihyperglycaemic medicinal product should be adjusted during therapy with the other medicinal product and on its discontinuation.
Interaction studies have shown that pioglitazone has no relevant effect on either the pharmacokinetics or pharmacodynamics of digoxin, warfarin, phenprocoumon and metformin.
Studies in man suggest no induction of the main inducible cytochrome P450, 1A, 2C8/9 and 3A4. In vitro studies have shown no inhibition of any subtype of cytochrome P450. Interactions with substances metabolised by these enzymes, e.g. oral contraceptives, cyclosporin, calcium channel blockers, and HMGCoA reductase inhibitors are not to be expected.
Pregnancy and Lactation
Pregnancy: Competact should not be used during pregnancy. If a pregnancy occurs, treatment with Competact should be discontinued.
Lactation: Both pioglitazone and metformin have been shown to be present in the milk of lactating rats. It is not known whether breast-feeding will lead to exposure of the infant to the medicinal product. Competact must therefore not be used in women who are breast-feeding.
See prescribing information for full details.
No data are available with regard to overdose of Competact.
In clinical studies, patients have taken pioglitazone at higher than the recommended highest dose of 45 mg daily. The maximum reported dose of 120 mg/day for four days, then 180 mg/day for seven days was not associated with any symptoms.
A large overdose of metformin (or coexisting risks of lactic acidosis) may lead to lactic acidosis which is a medical emergency and must be treated in hospital.
The most effective method to remove lactate and metformin is haemodialysis.
Storage: Store in a dry place below 25°C.